Clinical Review

Hong Chin, MD, PhD; Michael Baumann, MD; Nosrat Hillman, MD; and Reba Crowell, RN, NP

This article reviews the clinical presentation, prognosis, therapeutic strategies, and outcomes of thyroid .

rimary thyroid lymphoma is Figure 1. Table 1. Histologic subtypes of an uncommon and thyroid lymphoma1,3 includes < 5% of extranodal non-Hodgkin lymphoma and • Diffuse large B-cell lymphoma P 1,2 < 5% of all thyroid cancers. In the • MALT lymphoma past, it was often difficult to cor- rectly diagnose by fine-needle aspira- • Follicular lymphoma tion cytology (FNAC). Development • Hodgkin disease of immunocytochemical lymphoid • Small lymphocytic markers has improved the success MALT = mucosa-associated lymphoid tissue rate of an accurate diagnosis of thy- Pathologic image of thyroid lymphoma lymphoma. roid lymphoma. Although thyroid showing diffuse infiltration of atypical lymphoma is not a common cancer, cells consistent with B-cell lymphoma it is very important to distinguish pri- with no normal thyroid tissue present. commonly develop in organs other mary thyroid lymphoma from ana- than the thyroid gland). plastic thyroid carcinoma since the seen in the elderly in the seventh de- Thyroid lymphoma (Figure 1) is prognosis is very different; few pa- cade of life, although the age range a heterogeneous and diverse disease tients with anaplastic thyroid carci- can vary from 31 years to 82 years. entity and not a single disease. The noma survive beyond 2 years; while Almost all thyroid lymphomas are majority of thyroid lymphomas are of primary thyroid lymphoma generally B-cell non- and B-cell origin, and 5 distinctive histo- has a favorable outcome. This article are often associated with Hashimoto’s logic subtypes are recognized (Table reviews the clinical presentation, thyroiditis. Hodgkin lymphoma and 1).1,3 The most common and pre- prognosis, therapeutic strategies, and T-cell lymphomas of the thyroid are dominant histologic subtype is dif- outcomes of thyroid lymphomas. rare. fuse large B-cell lymphoma (DLBCL), which has a relatively monotonous Epidemiology Pathology architecture of large, abnormal lym- Primary thyroid lymphoma is rare Malignant tumors of the thyroid phoid cells and displays the most and represents 2% to 5% of extra- are largely divided into 2 categories aggressive clinical course. The sec- nodal non-Hodgkin lymphoma. based on the classification of the ond common subtype of histology is Thyroid lymphomas constitute < 5% World Health Organization: tumors mucosa-associated lymphoid tissue of all thyroid . Thyroid lym- that originate from the thyroid gland lymphoma (MALT), which shows phoma is 2 to 4 times more common proper and extraordinary tumors that small lymphocytes with plasmacytoid in women compared with men. Lym- appear as a thyroid gland malignancy features and has a relatively benign phomas of the thyroid are typically (such as thyroid lymphoma, which clinical course. MALT lymphomas are often associated with Hashimo- Dr. Chin is chief of radiation , Dr. Baumann is a staff physician in hematology and oncology, Dr. to’s thyroiditis. The development of Hillman is chief of pathology and laboratory medicine, and Ms. Crowell is a nurse practitioner in radia- MALT lymphoma from Hashimoto’s tion oncology, all at the Dayton VA Medical Center in Dayton, Ohio. Also, Dr. Chin is a clinical professor, Dr. Baumann is a professor of medicine, and Dr. Hillman is a clinical professor of pathology, all at Boon- thyroiditis takes a long time, some- shaft School of Medicine at Wright State University in Dayton, Ohio. times as long as 30 years.2 MALT

16 • FEDERAL PRACTITIONER • FEBRUARY 2013 lymphoma is generally character- Table 3. Presenting symptoms ized by an indolent clinical course, Table 2. B symptoms of and signs of thyroid lymphoma5 although transformation from MALT lymphomas lymphoma to aggressive lymphoma • Pel-Ebstein fever •  (82%-88%) 4 may occur in some cases. Follicular • Night sweats • Goiter (70%) lymphomas usually show a predomi- • > 10% unintentional weight nantly follicular pattern and often- • Dyspnea (65%) loss times a clinically protracted course •  (21%-53%) of disease; the response to therapy is short-lived, resulting in frequent sensation in the anterior neck region. • Hoarseness (25%-35%) recurrences. Hodgkin disease and The neck mass is usually smooth, small lymphocytic lymphoma are ex- bulky, and rubbery. Thyroid lympho- Figure 2. tremely rare and are not covered in mas frequently present on 1 side of this discussion. the thyroid gland. Hoarseness, dys- The diagnosis of DLBCL is rela- phagia, dyspnea, and stridor are also tively easy because of clear-cut patho- common presenting symptoms. The logic features of large, monotonous presence of constitutional symptoms atypical high-density cells. In con- (lymphoma’s B symptoms) are not trast, diagnosis of MALT lymphoma frequent, and few patients experi- is somewhat tricky, because of a ence B symptoms, such as fever, more heterogeneous overall picture night sweats, and weight loss (Table in addition to difficulty in demarcat- 2). The characteristic fever is a cyclic ing this entity from unmixed Hashi- fever over an average period of 1 or 2 moto’s thyroiditis. Furthermore, weeks, and it is specifically called Pel- Cytologic image of thyroid lymphoma sampling errors of tiny specimens Ebstein fever when associated with showing undifferentiated malignant could result in higher chances of lymphoma. neoplastic cells with no normal thyroid false negative reports, because many According to Sarinah and Hisham, tissue identified. MALT lymphomas occur in concert 65% of their thyroid lymphoma pa- with Hashimoto’s thyroiditis within tients were euthyroid, and 29% were ferentiate malignant lymphoma from a thyroid gland. The presence of a hypothyroid. The majority of their chronic lymphocytic thyroiditis. The lymphoepithelial lesion is not a spe- patients had a palpable goiter (Table sufficient tissue sampling is very im- cific finding of MALT lymphoma, al- 3).5 Four of 17 patients had clinically portant for appropriate interpretation though once it was considered to be a palpable cervical lymph nodes. How- of the histopathologic examination. diagnostic finding of thyroidal MALT ever, imaging studies showed the Recent advancement in immunocy- lymphoma. In order to distinguish presence of cervical lymph nodes in tochemical staining techniques and DLBCLs from MALT lymphomas and 11 patients.5 cytopathologic knowledge has en- also MALT lymphomas from Hashi- hanced the capacity to make an accu- moto’s disease, immunohistochemi- Diagnosis rate diagnosis of this rare entity. cal stains, flow cytometry analysis of Due to its rareness, thyroid lym- biopsy tissue, fine-needle aspiration phomas often create diagnostic and CYTOLOGY (FNA) sampling, and molecular ge- therapeutic difficulties. Until fine- Cytologic diagnosis of thyroid lym- netic analysis may be needed to aid needle aspiration biopsy (FNAB) was phoma requires careful analysis of in the diagnosis. developed in the late 1970s, thyroid morphologic, clinical, and immuno- lymphoma was frequently diagnosed phenotypic information. Fine-needle Clinical Presentation postoperatively, subsequent to thy- aspiration biopsy shows the replace- The most common presenting symp- roidectomy for presumed thyroid ment of the thyroid with neoplastic tom is a painless enlargement of the cancer. An ultrasound-guided FNAB lymphocytes by Papanicolaou stains neck (thyroid gland), which is typi- of an hypoechoic or pseudocystic le- (Figure 2). Certain characteristic cally seen in 30% to 50% of cases. sion is the preferred procedure since pathogenetic findings of large-cell Some patients may feel a pressure a blind FNAB is often unable to dif- lymphoma are large, monotonous ab-

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Table 4. International Prognostic Index (IPI) Figure 3. Factors Description Age > 60 years Performance status ECOG ≤ 2 Serum lactate dehydrogenase Abnormal Tumor stage III – IV Involved sites (No.) > 1

Source: N Engl J Med. 1993;329(14):987-994. ECOG = Eastern Cooperative Oncology Group Performance Status. Chest X-ray showing soft tissue density project- ing over the medial aspect of the left upper lung, Table 5. Prognostic group (IPI score) representing an underlying mass involving the Risk group IPI scores lower neck and upper .

Low 0-1 Figure 4. Low-intermediate 2 High-intermediate 3 High 4-5

Source: N Engl J Med. 1993;329(14):987-994. normal cells in a background of lym- rect diagnosis when im- phoglandular features, predominant munophenotyping was plasmacytoid lymphocytes, and spe- not applied, while 88% cific immunophenotyping findings. of cases (7 of 8 patients) The diagnosis of thyroid lymphoma were correctly diagnosed can be made accurately by FNAC in utilizing immunopheno- CT scan showing a large soft tissue mass in the a majority of patients, in correlation typing along with FNA. left side of the neck and superior mediastinum, with flow cytometry and immuno- For example, MALT which surrounds and arises from the left lobe of histochemical analysis technique. lymphoma can be linked the thyroid gland. In some difficult cases, however, a to 4 translocations and large-bore needle biopsy or excisional t(11;18) is the most com- biopsy may still be required for an ac- mon chromosomal translocation in IMAGING STUDY curate diagnosis, especially in small MALT lymphoma. A chest X-ray can show a mediasti- lymphocytic or MALT lymphomas in In cases of difficult morphologic nal mass or tracheal deviation (Fig- the setting of Hashimoto’s disease. problems, surface markers can pro- ure 3). Computed tomography and Continuous progress in immu- vide a valuable objective basis for re- magnetic resonance imaging (MRI) nophenotypic techniques, such as solving diagnostic dilemma. Markers, are the most useful imaging studies immunohistochemistry and flow cy- such as CD-22, CD-19, and CD-20 for diagnosis and staging of thyroid tometry, have remarkably improved are immunophenotypes of B-cell lymphomas (Figure 4). According to the accuracy of FNA for the diagno- lymphomas. Characteristic markers a study by Takashima and colleagues, sis of lymphoma (Table 4). Cha and of follicular center cell lymphoma are MRI was superior in correctly as- colleagues pioneered immunophe- CD-5-, CD-10+, and CD-23 +/- phe- sessing the extent of tumor infiltra- notyping in combination with FNA notypes; while the CD5-, CD10-, and tion to lymph nodes, surrounding in diagnosing thyroid lymphoma.6 CD23- phenotypes are typical mark- muscles, esophagus, internal jugu- Of their 4 patients, none had a cor- ers of MALT lymphoma. lar vein, and carotid artery.7 Ultra-

18 • FEDERAL PRACTITIONER • FEBRUARY 2013 Thyroid Lymphoma

sound is also a very useful imaging Figure 5. study in revealing a thyroid nodule that often clearly distinguishes from OVERALL SURVIVAL RATE (%) normal thyroid tissue and is also a Radiation therapy helpful tool in the successful localiza- tion and FNA procedures, compared 100% with random blind biopsies. How- 100 88% ever, an ultrasound is not a reliable 80% test in identifying lymphoma inva- 80 sion to surrounding structures such 60 Vigliotti as lymph nodes, the esophagus, and 63% carotid artery. 40 Ha TheraPEUTIC STRATEGy 20 The therapeutic strategy for this 0 tumor is somewhat contentious. In IE IIE the past, surgical resection was the 16,17 primary therapy. As malignant lym- Overall survival rates (stage IE vs IIE) after radiation therapy. phomas are very sensitive to both chemotherapy and radiotherapy, ra- indolent disease, as well as in pal- MALT lymphomas of various pre- diation treatment alone or combi- liating critical symptoms associated senting sites (stomach, orbit, sali- nation chemotherapy and radiation with large obstructive lymphomas. vary glands, thyroid glands, etc) therapy has become the standard of Past experience indicates a certain in patients who received radiation thyroid lymphoma treatment. The subgroup of early, localized stage IE therapy (median radiation dose of management of low-grade lympho- thyroid lymphomas showed good 3,000 cGy).11 Eighty-four of 85 pa- mas can be radiation therapy and response to surgery or radiation. In tients showed a complete response oral or intravenous chemotherapy. selected and ideal situations, sur- to radiation alone. No recurrences The management of DLBCL should gery may be recommended as a were observed in patients with thy- be combined-modality therapy with primary therapy of early stage lym- roid lymphoma.11 The more indo- radiation and chemotherapy, using phoma and favorable thyroid lym- lent lymphomas, MALT lymphomas the , doxoru- phomas, such as MALT subtype when localized to the thyroid (stage bicin, , and prednisone stage IE, only if the tumor can be IE), responded well to local therapy (CHOP) regimen.8 Surgical resec- completely resected with minimal alone. tion of the thyroid mass is no longer morbidity.9 a routine part of the management CHEMORADIATION THERAPY strategy. RADIATION THERAPY Currently, primary thyroid lym- In a report by Blair and colleagues, phoma is usually treated non- SURGERY from the Mayo Clinic, of 38 patients surgically once the diagnosis is In the past, surgery was the major treated with radiation therapy, over- established. For aggressive thyroid therapeutic strategy for thyroid lym- all disease-free survival at 5 years was lymphomas, a combined approach phoma treatment. However, surgery 59%.10 Fourteen patients experienced with chemotherapy and radiation is now playing a minor role as che- a recurrence, and 71% (10 patients) therapy is now a common approach motherapy and radiation therapy recurred in 2 or more sites. Patients for successful outcomes as systemic became more effective. Although received a radiation dose of 4,000 cGy chemotherapy reduces risk of dis- the role of surgery has become less (2,400-6,000 cGy) to the neck only or tant recurrences. Diffuse large B-cell important, surgery still plays cer- neck and mediastinum. They did not lymphoma, treated with aggressive tain imperative roles; specifically, recommend a split course of therapy therapy, is the most common and in surgical biopsy for establishing because of higher failure rates.10 major subtype, comprising roughly a correct diagnosis and a potential Tsang and colleagues reviewed 70% of thyroid lymphomas, and role in the local control of selected 103 cases with stage IE and IIE displays a more aggressive clinical

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Figure 6. B symptoms, and treatment modal- ity were all prognostic factors in the OVERALL SURVIVAL RATE (%) univariate analysis for OS, disease- 13 Chemoradiation therapy free survival, and local control. In multivariate analysis, OS was affected by age, B symptoms, lymph node 100% involvement, and tumor size, while IE disease-free survival and local control 100% were adversely related with B symp- Vigliotti toms and tumor size. Combined mo- dality treatment resulted in a better 64% Belal 5-year OS, disease-free survival, and IIE 81% local control, compared with single modality therapy. In contrast, Niitsu and colleagues found no significant 0 20 40 60 80 100 differences in either the OS or dis- ease-free survival according to age, Overall survival rates (stage IE vs IIE) after chemoradiation therapy.15,16 stage, lactic acid dehydrogenase level, or presence of bulky mass.14 As to course. Furthermore, almost 60% of apy.12 They also found that thyroid the International Prognostic Index these lymphomas present with dis- lymphomas confined to the neck (IPI), the low-intermediate risk cases seminated disease at the time of only had similar outcomes when showed significantly poorer progno- initial diagnosis. Accordingly, these treated with either combined modal- sis than did the low-risk cases in both lymphomas should be treated with ity or radiation alone. overall and disease-free survivals. combined modality of chemotherapy A clinical IPI was developed using and radiation. SeQUELAE OF THEraPY 5 factors (Table 4) and has become Previously, a popular combina- The most common adverse effects the standard for assessing clinical tion of multiagent chemotherapy (AEs) of radiotherapy are acute and prognosis and treatment stratifica- was CHOP, but recently rituximab transient skin and mucosal reactions, tion. One point was allocated for has been added to the CHOP com- erythematous skin changes, sore each factor and categorized into bination (R-CHOP). The current throat, esophagitis, dysphagia, and 4 prognostic groups; namely, low, standard regimen for chemotherapy rarely dry or moist desquamation. low-intermediate, high-intermediate, is R-CHOP. Sarinah and Hisham re- Late AEs include hypothyroidism and and high (Table 5). ported their experience with 15 pa- pneumonitis if mini-mantle field is Niitsu and colleagues reported an tients treated with R-CHOP with or used. In the worst-case scenario, fi- 84% and 90% 5-year progression-free without radiation therapy.5 All pa- brosis, mild skin atrophy, pigmenta- survival rate and OS rate, respec- tients showed an excellent response tion or telangiectasis, and neck edema tively, with a median follow-up pe- to therapy, and tumor size was rapidly could develop, but are extremely un- riod of 62 months in their study of decreased. At the time of their report, likely. Myelosuppression is the main 32 patients with stage I/IIE thyroid 14 patients were still alive with no ev- AE of chemotherapy. When used, car- DLBCL treated with combined ther- idence of recurrence, and the overall diotoxicity can be an important se- apy. A retrospective analysis of stage survival (OS) rate was 82%. quela of , depending on I and stage II thyroid lymphomas by Doria and colleagues reviewed the accumulated total dose. As a long- Onal and colleagues reported a 74% 211 cases of stage IE and stage IIE term sequela, second malignancy can and 71% 5- and 10-year OS rates and thyroid lymphoma in patients who be related with therapy. 68% and 64% disease-free survival were treated with a combined mo- rates, respectively.13,14 In conclusion, dality of therapy and found that dis- PROGNOSIS AND OUTCOMES multimodality combined therapy tant and overall failure rates were According to a study reported by demonstrated better outcomes for pa- significantly lower when patients Onal and colleagues, age, tumor tients with aggressive lymphoma but were treated with combined ther- size, stage, lymph node involvement, failed to improve OS and local control

20 • FEDERAL PRACTITIONER • FEBRUARY 2013 Thyroid Lymphoma

in indolent lymphoma patients. Se- Often, thyroid lymphoma patients adverse effects—before administering lected survival rates reported in the have had a prior history of Hashi- pharmacologic therapy to patients. literature for stage IE and stage IIE moto’s thyroiditis. Fine-needle aspira- lymphomas are shown in Figures 5 tion cytology has an established role 15-17 References and 6. in the diagnosis and management of 1. Derringer GA, Thompson LD, Frommelt RA, The presence of histopathologic thyroid lymphoma. Clinically, it can Bijwaard KE, Heffess CS, Abbondanzo SL. Malignant lymphoma of the thyroid gland: A clini- features of MALT are associated with be confused with anaplastic thyroid copathologic study of 108 cases. Am J Surg Pathol. a statistically significant factor in sur- carcinoma because of similar clini- 2000;24(5):623-639. 2. Pedersen RK, Pedersen NT. Primary non-Hodgkin’s vival of patients as well as a favor- cal characteristics of a rapid growing lymphoma of the thyroid gland: A population based able prognostic factor for high-grade neck mass. Although thyroid lym- study. Histopathology. 1996;28(1):25-32. 3. Thieblemont C, Mayer A, Dumontet C, et al. Pri- lymphomas. In the meantime, non- phoma is not a common cancer, it is mary thyroid lymphoma is a heterogeneous disease. MALT associated lymphomas have a very important to distinguish thyroid J Clin Endocrinol Metab. 2002;87(1):105-111. 4. Morgen EK, Geddie W, Boerner S, Bailey D, Santos poorer prognosis according to Laing lymphoma from anaplastic thyroid Gda C. The role of fine-needle aspiration in the di- and colleagues.18 The overall cause- carcinoma since the prognosis is very agnosis of thyroid lymphoma: A retrospective study of nine cases and review of published series. J Clin specific survival at 5 years for pa- different. Pathol. 2010;63(2):129-133. tients with non-Hodgkin lymphomas Most thyroid lymphomas are B- 5. Sarinah B, Hisham AN. Primary lymphoma of the thyroid: Diagnostic and therapeutic considerations. of MALT origin was 90% compared cell origin lymphomas and mostly Asian J Surg. 2010;33(1):20-24. with 55% for those without evidence DLBCL. The second most common 6. Cha C, Chen H, Westra WH, Udelsman R. Primary thyroid lymphoma: Can the diagnosis be made of MALT origin. histologic subtype is MALT lym- solely by fine-needle aspiration? Ann Surg Oncol. phoma. The choice of treatment 2002;9(3):298-302. 7. Takashima S, Nomura N, Noguchi Y, Matsuzuka FOLLOW-UP AND SURVEILLANCE is based on the histologic subtype, F, Inoue T. Primary thyroid lymphoma: Evalua- Most treatment failures seem to de- stage, and tumor bulkiness. Fortu- tion with US, CT, and MRI. J Comput Assist Tomogr. 1995;19(2):282-288. velop within the first 2 years after nately, the majority of thyroid lym- 8. Ansell SM, Grant CS, Habermann TM. Primary thy- therapy, although late recurrences phoma presents with stage I and stage roid lymphoma. Semin Oncol. 1999;26(3):316-323. 9. Widder S, Pasieka JL. Primary thyroid lymphomas. can occur. Regular follow-up is re- II disease. The 5-year survival rate is Curr Treat Options Oncol. 2004;5(4):307-313. quired for early detection of recur- about 80% for stage IE, 50% for stage 10. Blair TJ, Evans RG, Buskirk SJ, Banks PM, Earle JD. Radiotherapeutic management of primary rent disease, as well as prompt and IIE, and < 36% for stage IIIE and thyroid lymphoma. Int J Radiat Oncol Biol Phys. appropriate management of hypothy- stage IVE. Several studies reported 1985;11(2):365-370. 11. Tsang RW, Gospodarowicz MK, Pintilie M, et al. Local- roidism and hypocalcemia. Serum an advantage of multimodality using ized mucosa-associated lymphoid tissue lymphoma calcium and parathyroid hormone combined chemotherapy and radia- treated with radiation therapy has excellent clinical outcome. J Clin Oncol. 2003;21(22):4157-4164. should be monitored. Prolonged, tion therapy, which is the mainstay of 12. Doria R, Jekel JF, Cooper DL. Thyroid lymphoma: lifelong follow-up seems reason- thyroid lymphoma management. l The case of combined modality therapy. Cancer. 1994;73(1):200-206. able as late relapses and second ma- Author disclosures 13. Onal C, Li YX, Miller RC, et al. Treatment results lignancies have been reported. At and prognostic factors in primary thyroid lymphoma The authors report no actual or poten- patients: A rare cancer network study. Ann Oncol. each follow-up visit, a careful his- tial conflicts of interest with regard to 2011;22(1):156-164. tory and a complete physical ex- 14. Niitsu N, Okamoto M, Nakamura N, Nakamine H, this editorial. Bessho M, Hirano M. Clinicopathologic correlations amination should be performed. of stage IE/IIE primary thyroid diffuse large B-cell The first follow-up visit should be Disclaimer lymphoma. Ann Oncol. 2007;18(7):1203-1208. 15. Belal AA, Allam A, Kandil A, et al. Primary thyroid 4 to 6 weeks after completion of The opinions expressed herein are those lymphoma: A retrospective analysis of prognostic treatment and then patients should of the authors and do not necessarily factors and treatment outcome for localized inter- mediate and high grade lymphoma. J Clin Oncol. be followed every 3 to 4 months reflect those of Federal Practitioner, 2001;24(3):299-305. for the first year. After the first Quadrant HealthCom Inc., a division 16. Vigliotti A, Kong JS, Fuller LM, Velasquez WS. Thy- roid lymphomas stages IE and IIE: Comparative year, patients should be seen every of Frontline Medical Communications results for radiotherapy only, combination chemo- 6 months for the next 2 to 3 years, Inc, the U.S. Government, or any of its therapy only, and multimodality therapy. Int J Radiat Oncol Biol Phys. 1986;12(10):1807-1812. and then annually thereafter. agencies. This article may discuss un- 17. Ha CS, Shadle KM, Medeiros LJ, et al. Localized labeled or investigational use of certain non-hodgkin lymphoma involving the thyroid gland. Cancer. 2001;91(4):629-635. SUMMARY drugs. Please review complete prescrib- 18. Laing RW, Hoskin P, Hudson BV, et al. The signifi- Thyroid lymphoma is a rare cancer ing information for specific drugs or cance of MALT histology in thyroid lymphoma: A review of patients from the BNLI and Royal of the thyroid gland that tends to be drug combinations—including indica- Marsden Hospital. Clin Oncol (R Coll Radiol). prevalent in the elderly and women. tions, contraindications, warnings, and 1994;6(5):300-304.

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